Our laboratory has focused on discovering genes that are important for regulating iron homeostasis, with the overall goal of understanding human iron disorders. We have used animal models with inherited iron deficiency anemia to identify key components of iron transport pathways. We have also identified genes defective in human patients with inherited iron disorders. In the first cycle of this grant, we turned our attention to the discovery of novel genes that play more subtle roles in iron biology, reasoning that mouse genetics could be used as a tool not only to discover major components of iron transport and regulatory pathways, but also minor components that become important as modifiers of iron status. However, we still lack a complete understanding of genetic factors leading to variability in clinical presentations among human patients with iron disorders. The technology to carry out modifier gene mapping experiments has improved over the past five years, allowing novel approaches to this problem. This proposal describes two gene discovery experiments that will aid in the identification of additional candidate genes. Our overall hypothesis is that genes that modify iron stores in mice also modify the clinical expression of iron disorders in humans. Towards this end, we will (1) identify genes responsible for quantitative trait loci apparent in advanced intercross mouse lines with variable tissue iron content and (2) carry out genetic screens for novel genes involved in iron homeostasis using mice lacking Tmprss6, a key inhibitor of production of the iron regulatory hormone hepcidin. These complementary approaches should enhance our understanding of iron homeostasis and, importantly, yield new candidates for genes that determine clinical variability in the incidence and severity of iron disorders. PUBLIC HEALTH RELEVANCE: Iron overload and iron deficiency disorders are common in human populations. There is strong evidence that genetic factors influence which individuals are most severely affected. This application proposes two complementary approaches to identify those genetic factors, taking advantage of striking similarities in iron metabolism between humans and mice. Completion of this work should aid us in predicting which patients will need aggressive therapy and which can be managed conservatively